Cytotoxicity targeting chimeras for fibroblast activation protein-expressing cells

Abstract

The present disclosure relates to heterobifunctional molecules, referred to as cytotoxicity targeting chimeras (CyTaCs) or antibody recruiting molecules (ARMs) that are able to simultaneously bind a target cell-surface protein as well as an exogenous antibody protein. The present disclosure also relates to agents capable of binding to a receptor on a surface of a pathogenic cell and inducing the depletion of the pathogenic cell in a subject for use in the treatment of cancer.

1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
       
       
         
           
           
               
               
           
         
         
           T is 
           R 1  is C 1-4  alkyl or C 3-6  cycloalkyl; 
           R 2  and R 3  are each independently F or H; 
           L is a divalent linker of Formula (L-e), (L-p), (L-q), or (L-r): 
         
       
       
         
           
           
               
               
           
         
         
            wherein n is an integer of 12 to 50; 
         
       
       
         
           
           
               
               
           
         
         
            or a stereoisomer thereof,
 wherein:
 Ring A, Ring B, Ring C, and Ring D are each independently C 4-6  cycloalkylene; 
 L 1a , L 3a , and L 4 a are each independently C 3-5  linear alkylene, wherein 1 or 2 methylene units are replaced with —O— or —NR a —; 
 each R a  is independently hydrogen or C 1-3  alkyl; and 
 L 2a  is —O—, —NHC(O)—, or —CH 2 —O—; 
 
 
         
       
       
         
           
           
               
               
           
         
         
           
             
                wherein n is an integer of 10 to 30; or 
             
           
         
       
       
         
           
           
               
               
           
         
         
           
             
                wherein n is an integer of 10 to 30; 
             
             wherein each 
           
         
       
       
         
           
           
               
               
           
         
         
           
              represents a covalent bond to the Y group of Formula (I), or when Y is a bond, a covalent bond to the T group of Formula (I), and each 
           
         
       
       
         
           
           
               
               
           
         
         
           
              represents a covalent bond to the methylene group of Formula (I); and 
           
           Y is a bond or a divalent spacer moiety of one to twelve atoms in length. 
         
       
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is —CH 3 . 
     
     
         3 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein both R 2  and R 3  are F, or both R 2  and R 3  are H. 
     
     
         4 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is a divalent linker of Formula (L-p-i): 
       
         
           
           
               
               
           
         
       
       or a stereoisomer thereof,
 wherein L 1a , L 3a , L 4a , L 2a , 
 
       
         
           
           
               
               
           
         
       
       and are as defined for Formula (L-p). 
     
     
         5 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is a divalent linker of Formula (L-p-ii): 
       
         
           
           
               
               
           
         
       
       or a stereoisomer thereof,
 wherein p is 1, 2, or 3; m is 1, 2, or 3; n is 1, 2, or 3; and 
 
       
         
           
           
               
               
           
         
       
       are as defined for Formula (L-p). 
     
     
         6 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is a divalent linker of Formula (L-p) having the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is selected from a bond; —NH—; —(C 1-12  alkylene)-, wherein 1, 2, or 3 methylene units are replaced with —O—, —NH—, —N(CH 3 )—, —C(O)—, —NHC(O)—, —C(O)NH—, —(C 3-6  cycloalkylene)-, —(C 3-6  cycloalkenylene)-, 3- to 6-membered heterocycloalkylene, arylene, or heteroarylene; or —(C 2-12  alkenylene)-, wherein 1, 2, or 3 methylene units are replaced with —O—, —NH—, —N(CH 3 )—, —C(O)—, —NHC(O)—, —C(O)NH—, —(C 3-6  cycloalkylene)-, —(C 3-6  cycloalkenylene)-, 3- to 6-membered heterocycloalkylene, arylene, or heteroarylene. 
     
     
         8 . (canceled) 
     
     
         9 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 1 , wherein the compound is a compound in Table 1 or a pharmaceutically acceptable salt thereof. 
     
     
         11 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         12 . A method of treating and/or preventing a disease or disorder in a patient in need thereof, the method comprising: administering to the patient a therapeutically effective amount of the compound of  claim 1  and an anti-cotinine antibody, or antigen-binding fragment thereof, wherein the disease or disorder is selected from a cancer. 
     
     
         13 . (canceled) 
     
     
         14 . The method of  claim 12 , wherein the disease is a cancer that is a solid tumor. 
     
     
         15 . The method of  claim 12 , wherein the disease or disorder is a cancer selected from leukemia, lymphoma, lung cancer, hepatocellular carcinoma (HCC), colorectal cancer (CRC), cervical cancer, head and neck cancer, pancreatic cancer, prostate cancer, ovarian cancer, endometrial cancer, bladder cancer, bone cancer, esophageal cancer, gastric cancer, renal cancer, melanoma cancer, thyroid cancer, or breast cancer. 
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . A method of increasing antibody-dependent cell cytotoxicity (ADCC) of FAP-expressing cells, the method comprising: contacting the cells with an effective amount of the compound of any one of  claim 1  and an anti-cotinine antibody, or antigen-binding fragment thereof, wherein the FAP-binding moiety of the compound binds the FAP expressed on the cells. 
     
     
         19 . A method of depleting FAP-expressing cells, the method comprising: contacting the cells with an effective amount of the compound of  claim 1  and an anti-cotinine antibody, or antigen-binding fragment thereof, wherein the FAP-binding moiety of the compound binds the FAP expressed on the cells. 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 15 , wherein the anti-cotinine antibody has a heavy chain and a light chain, the heavy chain comprising a CDR1 having SEQ ID NO: 1, a CDR2 having SEQ ID NO: 2, and a CDR3 having SEQ ID NO: 3, and the light chain comprising a CDR1 having SEQ ID NO: 4, a CDR2 having SEQ ID NO: 5, and a CDR3 having SEQ ID NO: 6. 
     
     
         22 . The method of  claim 15 , wherein the anti-cotinine antibody has a heavy chain and a light chain, the heavy chain comprising a heavy chain variable region (VH) having SEQ ID NO: 7, and the light chain comprising a light chain variable region (VL) having SEQ ID NO: 8. 
     
     
         23 . (canceled) 
     
     
         24 . (canceled) 
     
     
         25 . The method of  claim 15 , wherein the anti-cotinine antibody has a heavy chain comprising SEQ ID NO: 9 and a light chain comprising SEQ ID NO: 10. 
     
     
         26 . A combination comprising the compound of  claim 1  and an anti-cotinine antibody, or antigen-binding fragment thereof. 
     
     
         27 . The combination of  claim 26 , wherein the anti-cotinine antibody has a heavy chain and a light chain, the heavy chain comprising a CDR1 having SEQ ID NO: 1, a CDR2 having SEQ ID NO: 2, and a CDR3 having SEQ ID NO: 3, and the light chain comprising a CDR1 having SEQ ID NO: 4, a CDR2 having SEQ ID NO: 5, and a CDR3 having SEQ ID NO: 6. 
     
     
         28 - 31 . (canceled)